Cytokines in milk and the role of TGF-beta.

Cytokines are required for normal growth and development of the mammary gland and TGF-ß prominently represents an established effector of apoptosis, e.g., during involution of the mammary gland. By the control of intracellular signaling pathways, including JAK/STAT, MAPK, PI-3K, and NF-κB, cytokines efficiently regulate cell proliferation and inflammation in the breast. Therefore, cytokines are discussed also in a context of malignant mammary growth. As a group of tissue hormones produced by somatic cells or by cells from the immune system, cytokines are defined by their immunomodulatory potential. Over the past 40 years, multiple cytokines were identified in colostrum and milk. Importantly, cytokines derived from mammary secretions after birth are required for maturation of the immune system in the developing gastrointestinal tract from the suckling. Moreover, recent studies have further assessed the particular interactions between probiotic bacterial strains and cytokines. In light of the increasing prevalence of inflammatory diseases of the gastrointestinal system, the effects of probiotic microorganisms during milk fermentation may have immunotherapeutic potential in the future.

Functional analysis of the IGF-system in milk.

The development of milk during evolution is considered a more recent step to provide the neonate with adequate amounts of energy, nutrients, and specific hormonal signals thereby, granting a fast and efficient rate of postnatal growth and development. Since the insulin- or the insulin-like growth factor (IGF) systems were evolved much earlier, it can be assumed that the functionality of the IGF-system has been integrated into the novel matrix milk containing casein and whey proteins from the beginnings. In fact, IGFs and IGF-binding proteins (IGFBPs) are abundantly present in milk, which is particularly true for fore-milk or colostrum and the potential effects of milk-borne IGF-compounds on the consuming organisms have in fact been addressed by several studies. Those studies examined, if orally administered IGFs can be absorbed by the consumer's gastro-intestinal tract and thus contribute e.g. to the somatic growth of infants. A second line of studies assessed local effects of milk-borne IGFs on growth and development of the gastro-intestinal tract itself. Finally, distinct functions of isolated IGF-compounds for growth and involution of the mammary gland have also been provided in the past. While the consumption of milk seems not to represent a major source of endogenous IGFs, accumulating evidence indicates secondary effects of milk on the endogenous IGF-system, which may be mediated by micronutrients such as branched amino acids and metabolic programming. By contrast, direct effects on growth and development of oesophageal and intestinal cells have been observed if IGFs were administered orally.

Cortical bone loss in androgen-deficient aged male rats is mainly caused by increased endocortical bone remodeling.

INTRODUCTION: Hypogonadism is considered to be one of the major risk factors for osteoporosis in men. Here, we sequentially studied the effects of androgen deficiency on cortical bone in aged orchiectomy (ORX) rats. MATERIALS AND METHODS: One hundred seventy 13-mo-old male Fischer-344 rats were either ORX or sham-operated. After in vivo fluorochrome labeling, groups of 8-15 SHAM and ORX rats each were killed at 2 wk and 1, 2, 3, 4, 6, and 9 mo after surgery. To examine the effects of testosterone replacement therapy, 9-mo-old ORX rats were supplemented with testosterone undecanoate at a weekly dose of 6 mg/kg for 4 mo. Cortical bone changes in the tibial shaft were monitored by pQCT analysis and by bone histomorphometry. RESULTS: SHAM rats did not show age-related bone loss at the tibial diaphysis. pQCT analysis and bone histomorphometry showed cortical bone osteopenia in ORX rats, beginning from 2 mo after surgery until the end of the study. Androgen deficiency induced a sustained decrease in periosteal bone formation during the first 4 mo after ORX. However, although periosteal expansion of the tibial shaft tended to be slower in ORX rats compared with SHAM controls, the reduction in total cross-sectional area in ORX animals reached statistical significance only at 4 mo after surgery. The major mechanism for cortical bone loss in aged ORX rats was a progressive expansion of the marrow cavity, which was associated with an initial increase in endocortical eroded perimeter at 1 and 2 mo after surgery, followed by a sustained increase in endocortical bone formation until the end of the study. All these changes were prevented in aged ORX rats receiving testosterone supplementation in an insulin-like growth factor system-independent fashion. CONCLUSIONS: We conclude that androgen deficiency-induced cortical bone loss in aged, nongrowing rats is mainly caused by augmented endocortical bone remodeling.